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- PDB-4mpv: Human beta-tryptase co-crystal structure with (2R,4S)-N,N'-bis[3-... -

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Basic information

Entry
Database: PDB / ID: 4mpv
TitleHuman beta-tryptase co-crystal structure with (2R,4S)-N,N'-bis[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]-4-hydroxy-2-(2-hydroxypropan-2-yl)-5,5-dimethyl-1,3-dioxolane-2,4-dicarboxamide
ComponentsTryptase alpha/beta-1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / coferon / alpha-hydroxyketone / small molecule inhibitor / drug discovery / self-assembly / crystal catalysis / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


tryptase / Activation of Matrix Metalloproteinases / extracellular matrix disassembly / serine-type peptidase activity / defense response / serine-type endopeptidase activity / proteolysis / extracellular space / extracellular region / identical protein binding
Similarity search - Function
Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Serine proteases, trypsin family, serine active site. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Trypsin-like serine proteases ...Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Serine proteases, trypsin family, serine active site. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Trypsin-like serine proteases / Thrombin, subunit H / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-2A4 / Tryptase alpha/beta-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.305 Å
AuthorsWhite, A. / Stein, A.J. / Suto, R.
CitationJournal: Acs Med.Chem.Lett. / Year: 2018
Title: Target-Directed Self-Assembly of Homodimeric Drugs Against beta-Tryptase.
Authors: Giardina, S.F. / Werner, D.S. / Pingle, M. / Foreman, K.W. / Bergstrom, D.E. / Arnold, L.D. / Barany, F.
History
DepositionSep 13, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 18, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 25, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tryptase alpha/beta-1
B: Tryptase alpha/beta-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,64010
Polymers54,9832
Non-polymers1,6578
Water2,774154
1
A: Tryptase alpha/beta-1
B: Tryptase alpha/beta-1
hetero molecules

A: Tryptase alpha/beta-1
B: Tryptase alpha/beta-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,28020
Polymers109,9664
Non-polymers3,31416
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation6_555-x,-x+y,-z+1/31
Buried area9840 Å2
ΔGint-163 kcal/mol
Surface area39160 Å2
MethodPISA
2


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4030 Å2
ΔGint-73 kcal/mol
Surface area20470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.490, 78.490, 165.481
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Tryptase alpha/beta-1 / Tryptase-1 / Tryptase I / Tryptase alpha-1


Mass: 27491.426 Da / Num. of mol.: 2 / Fragment: UNP residues 31-275
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TPS1, TPS2, TPSAB1, TPSB1 / Production host: Komagataella pastoris (fungus) / References: UniProt: Q15661, tryptase

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Non-polymers , 5 types, 162 molecules

#2: Chemical ChemComp-2A4 / (2R,4S)-N,N'-bis[3-({4-[3-(aminomethyl)phenyl]piperidin-1-yl}carbonyl)phenyl]-4-hydroxy-2-(2-hydroxypropan-2-yl)-5,5-dimethyl-1,3-dioxolane-2,4-dicarboxamide


Mass: 847.010 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C48H58N6O8
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 154 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence detailsN132K IS A NATURAL VARIANT.

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.68 Å3/Da / Density % sol: 54.04 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 4.6
Details: 30% PEG1500, 0.1 M sodium acetate, pH 4.6, 0.2 M ammonium sulfate, individual monocrystals equilibrated with 30% PEG1500, 0.1 M MES, pH 5.5, 0.2 M ammonium sulfate and soaked 20 hours in ...Details: 30% PEG1500, 0.1 M sodium acetate, pH 4.6, 0.2 M ammonium sulfate, individual monocrystals equilibrated with 30% PEG1500, 0.1 M MES, pH 5.5, 0.2 M ammonium sulfate and soaked 20 hours in same solution supplemented with compound 3A, VAPOR DIFFUSION, SITTING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 25, 2011 / Details: mirrors
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. all: 26782 / Num. obs: 26755 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4.8 % / Rmerge(I) obs: 0.094 / Χ2: 1.68 / Net I/σ(I): 10.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.3-2.384.80.63626181.5051100
2.38-2.484.80.51426101.4671100
2.48-2.594.80.40726471.4511100
2.59-2.734.90.28626341.4771100
2.73-2.94.80.21626601.5421100
2.9-3.124.80.14726531.6011100
3.12-3.444.80.126631.861199.9
3.44-3.934.70.08226922.19199.9
3.93-4.954.60.06127211.944199.9
4.95-504.50.05428571.77199.5

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.11data extraction
ADSCQuantumdata collection
HKL-2000data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.305→19.87 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.934 / WRfactor Rfree: 0.2191 / WRfactor Rwork: 0.1661 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8338 / SU R Cruickshank DPI: 0.2822 / SU Rfree: 0.22 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.282 / ESU R Free: 0.22 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2302 1337 5 %RANDOM
Rwork0.1723 ---
all0.1752 26779 --
obs0.1752 26530 99.07 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 121.24 Å2 / Biso mean: 47.8862 Å2 / Biso min: 25.47 Å2
Baniso -1Baniso -2Baniso -3
1-0.04 Å20.04 Å2-0 Å2
2--0.04 Å2-0 Å2
3----0.13 Å2
Refinement stepCycle: LAST / Resolution: 2.305→19.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3832 0 107 154 4093
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0194146
X-RAY DIFFRACTIONr_bond_other_d00.023796
X-RAY DIFFRACTIONr_angle_refined_deg1.8391.9875692
X-RAY DIFFRACTIONr_angle_other_deg3.53238732
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7635484
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.80123.371178
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.11815582
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.8911524
X-RAY DIFFRACTIONr_chiral_restr0.1010.2598
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0214632
X-RAY DIFFRACTIONr_gen_planes_other0.0230.02984
LS refinement shellResolution: 2.305→2.364 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.297 85 -
Rwork0.256 1733 -
all-1818 -
obs--97.27 %

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